Chronic myeloid leukemia (CML) is characterized by an initial chronic phase of expanded clonal hematopoiesis with continued differentiation into mature granulocytes. The chronic phase invariably progresses to blast crisis, a terminal stage resembling an acute leukemia. Allogeneic bone marrow transplantation (BMT) remain the only curative approaches for CML. Unfortunately, the effectiveness of allogeneic BMT is limited by the toxicity of graft-versus-host disease (GVHD) and the lack of histocompatible donors for most patients. Although T-lymphocyte depletion reduces GVHD, it is associated with an unacceptably high relapse rate. Therefore, new treatment approaches that offer a cure for patients with CML are needed; these approaches will only be developed from a better understanding of the basic biology of CML. The mechanisms responsible for the deregulated cell growth in CML has not been defined. Although CML has generally been considered a disease of abnormal myeloid proliferation, we found that the primary defect in CML is an enhancement of cell survival resulting from suppressed apoptosis. Furthermore, our preliminary data suggest that CML progenitors are hypersensitive to differentiation signals resulting in inhibition of proliferation in response to physiologic levels of growth factors. We postulate that the biological and clinical behavior of CML can be completely explained by the effects of BCR-ABL expression on cell survival and differentiation. The overall objective of this proposal is to investigate the mechanisms by which BCR-ABL induces CML. Specifically, we will elucidate the ability of specific growth factor to induce terminal differentiation and eradication of CML progenitors. We will also investigate the signal transduction pathways affected by BCR-ABL. These studies should provide the groundwork for novel therapeutic strategies for CML. We plan to evaluate the clinical effectiveness of myeloid growth factors as "differentiation therapy" in association with BMT for the treatment of CML. Because of its unique clinical behavior, the CML studies should also provide clues about normal hematopoiesis and other hematologic neoplasms.